First Responders present at Ground Zero during the first 72 hr after the WTC collapse have suffered significant damage to their respiratory health. This includes chronic disorders like sarcoid-like granulomatous pulmonary disease (SLGPD) and persistent airway hyperreactivity (AHR;defining feature of chronic asthma). While a number of animal studies using building-derived WTC dusts have been performed to better understand the etiology of some Responder ailments, they primarily used only a dust fraction (fine, d 2.5 5m diameter [da]) likely to be deposited in the lung, dusts collected after 9/13/01, or regimens that did not reflect exposure scenarios most Responders underwent. As significant coarse WTC dust particle deposition was found in the lungs of First Responders, and the alkalinity of WTC particles increases with da, we hypothesize that: (1) an increased presence of large (>2.5 5m) alkaline particles in their lungs contributed to the high incidence\severity of SLGPD and AHR;and, (2) a mechanism underlying these two disorders is that (A) the alkalinity of the large particles initially damaged the lung epithelium so that airway remodeling associated with persistent AHR was triggered and particle clearance was reduced, and (B) metals associated with the now-retained WTC particles exerted a variety of toxicities including granuloma induction and promotion of ongoing airway remodeling. As models for First Responders, rats will be exposed on 3 consecutive days (4 hr/d, via intratracheal inhalation) to WTC dusts (collected 9/12-13/01) and examined over a 1-yr post-exposure period. All dust concentrations used will be extrapolated from those present at Ground Zero on 9/11-13/01. Four interrelated Specific Aims are proposed to demonstrate that the: (1) increases in amounts of large (>2.5 5m) WTC particles in the lungs contribute to increases in AHR and SLGPD incidence\severity;(2) presence of alkaline portions of WTC dusts is critical to the observed AHR and SLGPD incidence\severity;(3) AHR incidence\severity after WTC dust exposure depends on initial airway epithelium damage and subsequent release of factors to promote remodeling;and, (4) SLGPD (and AHR) incidence\severity after WTC dust exposure is related to altered dust retention. These studies using an animal model, relevant WTC dusts, and relevant exposure scenarios will permit clarification of what role those WTC dusts inhaled during 9/11-13/01 may have had in the changes in Responders'respiratory health, provide important clues as to the etiology of the reported chronic lung disorders, and allow monitoring of effects from exposure to intact WTC dusts (or its large size fractions) on the initiation\progression of AHR and SLGPD. Data obtained here will provide valuable information about relation- ships between the physicochemical properties of building collapse-/demolition-associated dusts and toxicologic effects in the lungs. It is hoped that appropriate Investigators in Worker Safety\Emergency Planning and in Respiratory Medicine will then use this information to develop, respectively, prospective action plans and focused treatments to protect the respiratory health of firefighters/rescuers called to future building collapses. Public Health Relevance: The proposed studies seek to gain a better understanding of the bases for the increasing incidence and severity of two chronic lung disorders, AHR and SLGPD, in 9/11 First Responders. These studies which use an animal model, relevant WTC dusts, and relevant exposure scenarios will: permit clarification of what role those WTC dusts inhaled during 9/11-9/13/01 may have had in the changes in the Responders'respiratory health;provide important clues as to the etiology of some of these ongoing chronic lung disorders;and, allow monitor- ing of effects from exposure to intact WTC dusts (or its large size fractions) on the initiation\progression of AHR and SLGPD. Data obtained here will provide valuable information concerning relationships between physico- chemical properties of building collapse-/demolition-associated dusts and toxicologic effects in the lungs that appropriate Investigators in Worker Safety\Emergency Planning and in Respiratory Medicine could use to develop, respectively, prospective action plans and focused treatments to protect the respiratory health of firefighters, rescue personnel, and others who may likely be called to any future building collapse.